This invention relates to novel pyridazine derivatives, which have excellent inhibitory activity against interleukin-1xcex2 production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, and also to medicines containing them as effective ingredients.
In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, leukemia and the like, stimulation of interleukin-1xcex2 production, an inflammatory cytokine, is observed. This interleukin-1xcex2 serves to induce synthesis of an enzyme which is considered to take part in inflammation like collagenase and PLA2 and, when intra-articularly injected to animals, causes multiarticular destruction highly resembling rheumatoid arthritis. On the other hand, interleukin-1xcex2 is controlled in activity by interleukin-1xcex2 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted making use of recombinants of these bioactivity-inhibiting substances, anti-interleukin-1xcex2 antibodies and anti-receptor antibodies against various disease models, interleukin-1xcex2 has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1xcex2 inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids which are used for the treatment of rheumatism out of such many diseases have been reported to inhibit the production of interleukin-1xcex2. Even among medicaments currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to have inhibitory activity against interleukin-1xcex2 production although it is an immunoregulator. Inhibitory activity against interleukin-1xcex2 production is also observed on a group of compounds which are called xe2x80x9cCOX-2 selective inhibitorsxe2x80x9d,for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).
For all of these compounds, however, interleukin-1xcex2 production inhibitory activity is not their primary action so that their inhibitory activity against interleukin-1xcex2 production is lower than their primary action.
In recent years, increasingly active research is under way for the synthesis of compounds with a focus placed on inhibitory activity against interleukin-1xcex2 production. Inhibitors synthesized in such research can be classified into a group of compounds which inhibit the transfer process of an inflammatory signal to a cell nucleus and another group of compounds which inhibit an enzyme ICE that functions in the processing of a precursor of interleukin-1xcex2 Known examples of compounds presumed to have the former action include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 97/05878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
None of these compounds can however exhibit sufficient inhibitory activity against interleukin-1xcex2 production.
On the other hand, it is known that a variety of 5,6-diphenylpyridazine derivatives have analgesic and anti-inflammatory action (EUR. J. MED. CHEM., 14, 53-60, 1979) and also that 3,4,5,6-substituted pyridazine derivatives have inhibitory activity against interleukin-1xcex2 converting enzymes [Japanese Patent Application Laid-Open (Kokai) No. HEI 7-69894]. Absolutely nothing has however been known with respect to inhibitory activity of 2,4,6-substituted pyridazin-3-one derivatives against interleukin-1xcex2 production.
Accordingly, an object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1xcex2 production and also a medicine containing it as an effective ingredient.
Under such circumstances, the present inventors have proceeded with an extensive investigation. As a result, it has been found that pyridazine derivatives represented by the below-described formula (1) have excellent inhibitory activity against interleukin-1xcex2 production and are useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like, leading to the completion of the present invention.
Namely, the present invention provides a pyridazine derivative represented by the following formula (1): 
wherein R1 represents a lower alkoxyl group, a lower alkylthio group or a halogen atom; R2 represents a hydrogen atom, a lower alkoxyl group, a lower alkylthio group or a halogen atom; R3 represents a linear or branched lower alkyl or lower alkenyl group, which may have one or more substituents each independently selected from a hydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group, a substituted or unsubstituted aromatic group or a substituted or unsubstituted carbamoyl group; R4 represents a carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted thiocarbamoyl group, a substituted or unsubstituted amino group, or a substituted or unsubstituted ureido group; and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond; or a salt thereof.
Further, the present invention also provides a medicine comprising the pyridazine derivative (1) or the salt thereof as an effective ingredient.
Furthermore, the present invention also provides a pharmaceutical composition comprising the pyridazine derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the pyridazine derivative (1) or the salt thereof as a medicine.
In addition, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1xcex2 production, which comprises administering the pyridazine derivative (1) or the salt thereof.
The pyridazine derivative according to the present invention is represented by the formula (1). In the formula, illustrative of the lower alkoxyl groups represented by R1 and R2 can be those having 1 to 6 carbon atoms, for example, methoxy, ethoxy and propoxy. Illustrative of the lower alkylthio groups can be those having 1 to 6 carbon atoms, for example, methylthio, ethylthio and propylthio. Illustrative of the halogen atoms can be fluorine, chlorine, bromine and iodine.
Preferred as R1 is a fluorine atom, a lower alkoxyl group or a lower alkylthio group, while preferred as R2 is a hydrogen atom, a halogen atom or a lower alkoxyl group.
Examples of the lower alkyl group out of those represented by R3 can include linear or branched lower alkyl groups having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl. Examples of the lower alkenyl group can include linear or branched lower alkenyl groups having 2 to 9 carbon atoms, more preferably 2 to 6 carbon atoms and 1 to 3 double bonds, for example, ethenyl, propenyl and butenyl.
These lower alkyl groups and lower alkenyl groups may have one or more substituents each independently selected from a hydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group, a substituted or unsubstituted aromatic group, or a substituted or unsubstituted carbamoyl group.
Examples of the lower cycloalkyl group can include those having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Examples of the aromatic group can include aromatic hydrocarbon groups and aromatic heterocyclic groups, for example, phenyl, naphthyl and pyridyl, with phenyl and pyridyl being particularly preferred. These aromatic groups may each contain 1 to 3 substituents. Examples of such substituents can include halogens, nitro, amino, and aromatic-group-substituted carbonylamino groups. Illustrative of aromatic group(s) substituted on the carbonylamino group can be phenyl and pyridyl.
Illustrative of substituent(s) which the carbamoyl group may have can be lower alkyl groups, lower alkyl groups each of which may be substituted by one or more hydroxyl groups or aromatic groups, and aromatic groups each of which may be substituted by one or more lower alkylthio groups.
Further, examples of the halogen atoms, aromatic groups, lower alkyl groups and lower alkylthio groups can be similar ones as those exemplified above (including those exemplified as R1 and R2).
R3 may preferably be an alkyl group having 1 to 6 carbon atoms or a lower alkenyl group having 2 to 9 carbon atoms, which may have one or more substituents each independently selected from a hydroxyl group, a halogen atom, a cyano group or a lower cycloalkyl group; a phenyl or pyridyl group which may have 1 to 3 substituents each independently selected from a halogen atom, a nitro group, an amino group or an aromatic-group-substituted carbonylamino group; or a carbamoyl group which may have one or more substituents each independently selected from a lower alkyl groups, hydroxy lower alkyl group, an aromatic-group-substituted lower alkyl group or a lower alkylthiophenyl group.
Examples of the lower alkoxycarbonyl group out of those represented by R4 can include carbonyl groups each of which has an alkoxyl group having 1 to 6 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.
Examples of the substituent(s) in the substituted carbamoyl or thiocarbamoyl group can include lower alkyl groups, which may have one or more substituents such as aromatic groups, and aromatic groups.
Examples of the substituent(s) in the substituted amino group can include lower alkoxycarbonyl groups each of which may have one or more substituents such as aromatic groups; acyl groups; lower alkyl groups each of which may have one or more substituents such as aromatic groups; and lower alkylsulfonyl groups. Illustrative of the acyl groups can be those having 1-5 carbon atoms, for example, formyl, acetyl, propionyl and butyryl.
Examples of the substituent(s) in the substituted ureido group can include lower alkyl groups.
Incidentally, specific examples of the individual groups, such as the lower alkyl group, aromatic group and lower alkoxyl group, represented by R4 can be similar to those exemplified above with respect to R1, R2 and R3.
R4 may preferably be a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl or thiocarbamoyl group which may have one or more substitutents each independently selected from a lower alkyl group, an aromatic group or an aromatic-group-substituted lower alkyl group; an amino group which may have one or more substituents each independently selected from a lower alkoxycarbonyl group, an aromatic-group-substituted lower alkoxycarbonyl group, an acyl group, a lower alkyl group, an aromatic-group-substituted lower alkyl group or a lower alkylsulfonyl group; or a ureido group which may have one or more lower alkyl groups as substituents.
Further, the dashed line in the formula (1), namely, the carbon-carbon bond between the 4-position and the 5-position may preferably be a double bond.
Preferred examples of the pyridazine derivative (1) can include those represented by the same formula in which R1 represents a fluorine atom, a lower alkoxyl group or a lower alkylthio group; R2 represents a hydrogen atom, a halogen atom or a lower alkoxyl group; R3 represents a linear or branched lower alkyl group having 1 to 6 carbon atoms or a linear or branched lower alkenyl group having 2 to 9 carbon atoms, which may have one or more substitutents each independently selected from a hydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group; a phenyl or pyridyl group which may have 1 to 3 substituents each independently selected from a halogen atom, a nitro group, an amino group or an aromatic-group-substituted carbonylamino group; or a carbamoyl group which may be have one or more substituents each independently selected from a lower alkyl group, a hydroxy lower alkyl group, an aromatic-group-substituted lower alkyl group or a lower alkylthiophenyl group; and R4 represents a carboxyl group; a lower alkoxycarbonyl group; a carbamoyl or thiocarbamoyl group which may have one or more substituents each independently selected from a lower alkyl group, an aromatic group or an aromatic-group-substituted lower alkyl group; an amino group which may be have one or more substitutents each independently selected from a lower alkoxycarbonyl group, an aromatic-group-substituted lower alkoxycarbonyl group, an acyl group, a lower alkyl groups, an aromatic-group-substituted lower alkyl group or a lower alkylsulfonyl group; or a ureido group which may have one or more lower alkyl groups as substituents.
Specific preferred examples can include 2-isobutyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-(cyclopropylmethyl)-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-(cyclopropylmethyl)-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one, 2-(cyclopropylmethyl)-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one, 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one, or 2-(4-chlorocinnamyl)-4-formylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one.
No particular limitation is imposed on the salt of the pyridazine (1), said salt also pertaining to the present invention, insofar as it is a pharmacologically acceptable salt. Illustrative can be acid addition salts of mineral acids, such as the hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; and acid addition salts of organic acids, such as the benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate and citrate.
Further, the compounds according to the present invention may exist in the form of solvates represented by hydrates and also in the form of keto-enol tautomers. Such solvates and isomers should also be encompassed by the present invention.
The pyridazine derivatives (1) according to the present invention can be prepared, for example, by the following processes. 
wherein R5 represents a lower alkyl group, R6 and R7 each independently represent a hydrogen atom, a substituted or unsubstituted lower alkyl group or an aromatic group, R8 represents a substituted or unsubstituted lower alkyl group, R9 represents a substituted or unsubstituted lower alkyl group, R10 represents an acyl group, a lower alkylsulfonyl, or a substituted or unsubstituted carbamoyl group, X represents an oxygen atom or a sulfur atom, and R1, R2 and R3 have the same meanings as defined above.
A description will be made specifically about respective preparation processes of compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h) and (1i) among the pyridazine derivatives (1).
(1) Preparation of compounds (1a) of the formula (1) in which R4 is a lower alkoxycarbonyl group and a double bond is formed between the 4-position and the 5-position:
Each compound (1a) can be obtained by reacting a compound (3), which has been obtained by esterifying a compound (2) by a method known per se in the art, with a compound (5), which is represented by R3-Y wherein R3 has the same meaning as defined above and Y represents a halogen atom or an OH group already converted into a reactive ester group, in the presence of a base in a solvent.
The compound (2) employed here can be prepared, for example, by the process disclosed in Japanese Patent Application Laid-Open (Kokai) No. HEI 7-69891.
As the reactive ester group of the hydroxyl group, a tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group or the like is preferred. A compound which contains such a group can be obtained by reacting para-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride or the like with a hydroxyl derivative in the presence of a base such as pyridine, triethylamine or collidine. The reaction is brought to completion at xe2x88x9215 to 50xc2x0 C. in 1 to 50 hours, preferably at xe2x88x925 to 30xc2x0 C. in 1 to 10 hours. As a solvent, pyridine, tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or the like can be used.
Examples of the base for use in the reaction between the compound (3) and the compound (5) can include inorganic bases such as potassium carbonate and sodium carbonate and organic bases such as pyridine, triethylamine, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). Usable examples of the solvent can include N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl ethyl ketone, chloroform, methylene chloride, toluene, and benzene. The reaction is brought to completion at 20 to 150xc2x0 C. in 1 to 20 hours, preferably at 50 to 130xc2x0 C. Among the compounds (1a), one containing an aminophenylalkyl group as R3 can be obtained by reducing the nitro group of a compound (1a) in which R3 is a nitrophenylalkyl group. Further, N-acylation of the aminophenylalkyl group makes it possible to obtain a compound in which R3 is an N-acylaminophenylalkyl group.
(2) Preparation of compounds (1b) of the formula (1) in which R4 is a substituted or unsubstituted carbamoyl group and a double bond is formed between the 4-position and the 5-position:
Each compound (1b) can be obtained by reacting in a solvent the compound (3) with an amine, which is represented by R6R7NH2 in which R6 and R7 have the same meanings as defined above, to give the compound (4), followed by reacting it as a raw material in a similar manner as in the reaction between the compound (3) and the compound (5). In the reaction between the compound (3) and the amine, it is preferable to use the amine in an amount of from 1 to 30 equivalents, especially from 2 to 15 equivalents relative to the compound (3). Usable examples of the solvent can include methanol, ethanol, isopropanol, tetrahydrofuran, and N,N-dimethylformamide. The reaction is brought to completion at xe2x88x9210 to 200xc2x0 C. in 0.5 to 24 hours, preferably at 20 to 150xc2x0 C. in 0.5 to 3 hours.
On the other hand, the reaction between the compound (4) and the compound (5) is brought to completion at 20 to 150xc2x0 C. in 1 to 20 hours, preferably at 50 to 130xc2x0 C. in 2 to 10 hours.
Among the compounds (1b), one containing an arylalkylcarbamoylalkyl group or a hydroxyalkylcarbamoylalkyl group as R3 can be obtained by reacting an arylalkylamine or a hydroxyalkylamine with a compound (1b) in which R3 is an alkoxycarbonylalkyl group.
Each of the compounds (1b) can also be obtained by reacting the compound (1a) as a raw material in a similar manner as in the reaction conducted upon conversion of the compound (3) into the compound (4).
(3) Preparation of compounds (1i) of the formula (1) in which R4 is a substituted or unsubstituted carbamoyl group and a single bond is formed between the 4-position and the 5-position:
Each compound (1i) can be obtained by subjecting the compound (1b) to catalytic reduction in a manner known per se in the art. The reaction can be conducted by effecting hydrogenation at room temperature or under heating in the presence of palladium on charcoal, Raney nickel or the like as a catalyst in a solvent such as methanol, ethanol or ethyl acetate.
(4) Preparation of compounds (1c) of the formula (1) in which R4 is a carboxyl group and a double bond is formed between the 4-position and the 5-position:
Each compound (1c) can be obtained by hydrolyzing the compound (1a) under acidic or basic conditions in a solvent by a method known per se in the art.
Examples of an acid can include hydrochloric acid, sulfuric acid and trifluoroacetic acid, while examples of a base can include sodium hydroxide, potassium hydroxide and barium hydroxide. Usable examples of the solvent can include mixed solvents of water with methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide and the like. The reaction is brought to completion at 0 to 150xc2x0 C. in 10 minutes to 5 hours, preferably at 20 to 100xc2x0 C. in 30 minutes to 2 hours.
(5) Preparation of compounds (1d) of the formula (1) in which R4 is a substituted or unsubstituted alkoxycarbonylamino group and a double bond is formed between the 4-position and the 5-position:
Each compound (1d) can be obtained by reacting a compound (1c) with an alcohol, which is represented by R8OH in which R8 has the same meaning as defined above, and diphenylphosphoryl azide (DPPA) in the presence of a base in a solventless manner or in a solvent.
Examples of the solvent can include benzene and toluene. Usable examples of the base can include triethylamine. The reaction is brought to completion at 50 to 150xc2x0 C. in 0.5 to 24 hours, preferably at 80 to 120xc2x0 C. in 1 to 8 hours.
(6) Preparation of compounds (1e) of the formula (1) in which R4 is an amino group substituted by a substituted or unsubstituted lower alkyl group and a lower alkoxycarbonyl group and a double bond is formed between the 4-position and the 5-position:
Each compound (1e) can be obtained by reacting a compound (1d) with a compound, which is represented by R9-Y wherein R9 and Y have the same meanings as defined above, in the presence of a base in a solvent. The reaction can be conducted in a similar manner as the above-described reaction between the compound (3) and the compound (5).
(7) Preparation of compounds (1f) of the formula (1) in which R4 is an amino group substituted by a substituted or unsubstituted lower alkyl group and a double bond is formed between the 4-position and the 5-position:
Each compound (1f) can be obtained by hydrolyzing a compound (1e) under acidic or basic conditions in a solvent by a method known per se in the art
Examples of an acid can include hydrochloric acid and sulfuric acid, while examples of a base can include sodium hydroxide, potassium hydroxide and barium hydroxide. Usable examples of the solvent can include mixed solvents of water with methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide and the like. The reaction is brought to completion at 0 to 180xc2x0 C. in 10 minutes to 24 hours, preferably at 20 to 120xc2x0 C. in 0.5 to 8 hours.
(8) Preparation of compounds (1g) of the formula (1) in which R4 is an amino group and a double bond is formed between the 4-position and the 5-position:
Each compound (1g) can be obtained by hydrolyzing the compound (1d) under acidic or basic conditions in a solvent by a method known per se in the art.
Examples of an acid can include hydrochloric acid and sulfuric acid, while examples of a base can include sodium hydroxide, potassium hydroxide and barium hydroxide. Usable examples of the solvent can include mixed solvents of water with methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide and the like. The reaction is brought to completion at 0 to 180xc2x0 C. in 10 minutes to 24 hours, preferably at 2 to 120xc2x0 C. in 0.5 to 8 hours.
(9) Preperation of compounds (1h) of the formula (1) in which R4 is an acylamino group, a lower alkylsulfonylamino group or a substituted or unsubstituted ureido group and a double bond is formed between the 4-position and the 5-position:
(i) Each compound (1h) in which R4 is an acylamino group can be obtained by reacting a compound (1g) with a compound, which is represented by R11COX or (R11CO)2O wherein R11 represents a lower alkyl group, an aryl group or a lower aralkyl group and X represents a halogen atom, in the presence of a base in a solvent.
Examples of the solvent can include pyridine, tetrahydrofuran, dioxane, ethyl acetate, chloroform, toluene and benzene. It is also possible to use a mixed solvent of water and ethyl acetate, chloroform, toluene, benzene or the like. Usable examples of the base can include organic bases such as pyridine, triethylamine and DBU and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. The reaction is brought to completion at xe2x88x9215 to 100xc2x0 C. in 1 to 50 hours, preferably at xe2x88x925 to 50xc2x0 C. in 2 to 25 hours.
(ii) Each compound (1h) in which R4 is a lower alkylsulfonylamino group can be obtained by reacting, in a solvent and in the presence of a base, the compound (1g) with 2 equivalents or more of a compound, which is represented by R11SO2X or (R11SO2)2O wherein R11 and X have the same meanings as defined above in a similar manner as in the process (i), to give a di(lower alkylsulfonyl)amino derivative, followed by hydrolyzing it under basic conditions in a solvent.
Examples of the solvent for use in the hydrolysis can include mixed solvents of water and methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide and the like. Usable examples of the base can include organic bases such as pyridine and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. The reaction is brought to completion at xe2x88x9215 to 100xc2x0 C. in 10 minutes to 10 hours, preferably at 0 to 80xc2x0 C. in 0.5 to 5 hours.
(iii) Each compound (1h) in which R4 is a substituted or unsubstituted ureido group can be obtained by reacting the compound (1g) with a compound, which is represented by R11NCO wherein R11 has the same meaning as defined above, in a solvent.
Usable examples of the solvent can include toluene and benzene. The reaction is brought to completion at 20 to 150xc2x0 C. in 0.5 to 30 hours, preferably at 50 to 120xc2x0 C. in 1 to 8 hours.
(10) Compounds (1b) or compounds (1i) of the formula (1) in each of which R4 is a substituted or unsubstituted thiocarbamoyl group can each be obtained by converting X of the compound (1b) or the compound (1i), in which X is an oxygen atom, into a sulfur atom. For example, X in the compound (1b) in which X is an oxygen atom can be converted into a sulfur atom by reacting the compound (1b) with Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) in a solvent. It is preferred to use Lawesson""s reagent in 0.5 to 3 equivalents, notably 1 to 1.5 equivalents relative to the compound (1b). The reaction is brought to completion at 30 to 150xc2x0 C. in 1 to 20 hours, preferably at 50 to 100xc2x0 C. in 5 to 15 hours. Usable examples of the solvent can include toluene and xylene.
(11) Preparation of compounds (1i) of the formula (1) in which R4 is a substituted or unsubstituted carbamoyl group or thiocarbamoyl group and a single bond is formed between the 4-position and the 5-position:
Each compound (1i) can be prepared by hydrogenating the compound (1b), in which R4 is a substituted or unsubstituted carbamoyl group or thiocarbamoyl group, in a solvent in the presence of palladium on charcoal or the like as a catalyst. Usable examples of the solvent can include methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, and N,N-dimethylformamide. The reaction is brought to completion at 15 to 200xc2x0 C. in 1 to 50 hours, preferably at 50 to 120xc2x0 C. in 2 to 20 hours.
The intermediates and target compounds obtained in the above-described individual reactions can be separated and purified by purification methods commonly employed in organic synthesis chemistry, for example, by subjecting them to filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic treatment, and the like. The intermediates may be provided for the next reactions without purifying them specifically. Further, they may also be obtained as solvates of solvents such as reaction solvents or recrystallization solvents, especially as hydrates.
The pyridazine derivatives (1) and their salts according to the present invention, which are available as described above, have excellent inhibitory activity against interleukin-1xcex2 production, and are useful for the prevention and treatment of diseases caused by stimulation of interleukin-1xcex2 production, for example, immune system diseases, inflammatory diseases, ischemic diseases, osteoporisis, ichorrhemia and the like, especially as medicines such as preventives and therapeutics for rheumatism, immune deficiency syndrome, arthritis, inflammatory colitis, ischemic heart diseases, ischemic encephalopathy, ischemic nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, leukemia and the like or as interleukin-1xcex2 production inhibitors.
Medicines according to the present invention contain the pyridazine derivatives (1) or their salts as effective ingredients. Their administration routes can include, for example, oral administration by tablets, capsules, granules, powders, syrups or the like and parenteral administration by intravenous injections, intramuscular injections, suppositories, inhalants, transdermal preparations, eye drops, nasal drops or the like. Upon formulation of pharmaceutical compositions of these various unit dosage forms, the effective ingredients can be used singly or in combination with pharmaceutically acceptable carriers, for example, excipients, binders, extenders, disintegrators, surfactants, lubricants, dispersants, buffers, preservatives, corrigents, perfumes, coating agents, vehicles, diluents or the like, as desired.
The dosage of each medicine according to the present invention varies depending on the age, body weight, conditions, administration form, administration frequency and the like. In general, however, it is preferred to orally or parenterally administer to an adult the effective ingredient in an amount of about 0.01 to 1,000 mg, preferably 0.1 to 100 mg per day at once or in several portions.